Brietta M. Oaks

Folate intake, post–folic acid grain fortification, and pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

BACKGROUND Folate plays a critical role in DNA methylation, synthesis, and repair. Several epidemiologic studies suggest that higher folate intake is associated with decreased pancreatic cancer risk. OBJECTIVE We investigated the association between dietary folate intake and pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. DESIGN Dietary data were collected with the use of a self-administered food-frequency questionnaire (1998-2005). Among the 51,988 male and 57,187 female participants, aged 55-74 y at enrollment, with complete dietary and multivitamin information, 162 men and 104 women developed pancreatic cancer during follow-up (January 1998 to December 2006; median: 6.5 y). We used Cox proportional hazards regression with age as the time metric to calculate hazard ratios (HRs) and 95% CIs. RESULTS The highest compared with the lowest quartile of food folate was associated with a significantly decreased pancreatic cancer risk among women (> or = 253.3 compared with < or = 179.1 microg/d; HR = 0.47; 95% CI: 0.23, 0.94; P for trend: 0.09) but not among men (> or = 229.6 compared with < or = 158.0 microg/d; HR = 1.20; 95% CI: 0.70, 2.04; P for trend: 0.67; P for interaction by sex: 0.03). There was also a significant inverse trend in risk of pancreatic cancer across increasing quartiles of total folate in women (P for trend: 0.04) but not in men (P for trend: 0.65). Folic acid supplements were not associated with pancreatic cancer. CONCLUSION These findings support an association between higher food and total folate intakes and decreased risk of pancreatic cancer in women but not in men.

U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation

Both iron deficiency (ID) and excess can lead to impaired health status. There is substantial evidence of a U-shaped curve between the risk of adverse birth outcomes and maternal hemoglobin concentrations during pregnancy; however, it is unclear whether those relations are attributable to conditions of low and high iron status or to other mechanisms. We summarized current evidence from human studies regarding the association between birth outcomes and maternal hemoglobin concentrations or iron status. We also reviewed effects of iron supplementation on birth outcomes among women at low risk of ID and the potential mechanisms for adverse effects of high iron status during pregnancy. Overall, we confirmed a U-shaped curve for the risk of adverse birth outcomes with maternal hemoglobin concentrations, but the relations differ by trimester. For low hemoglobin concentrations, the link with adverse outcomes is more evident when hemoglobin concentrations are measured in early pregnancy. These relations generally became weaker or nonexistent when hemoglobin concentrations are measured in the second or third trimesters. Associations between high hemoglobin concentration and adverse birth outcomes are evident in all 3 trimesters but evidence is mixed. There is less evidence for the associations between maternal iron status and adverse birth outcomes. Most studies used serum ferritin (SF) concentrations as the indicator of iron status, which makes the interpretation of results challenging because SF concentrations increase in response to inflammation or infection. The effect of iron supplementation during pregnancy may depend on initial iron status. There are several mechanisms through which high iron status during pregnancy may have adverse effects on birth outcomes, including oxidative stress, increased blood viscosity, and impaired systemic response to inflammation and infection. Research is needed to understand the biological processes that underlie the U-shaped curves seen in observational studies. Reevaluation of cutoffs for hemoglobin concentrations and indicators of iron status during pregnancy is also needed.

Maternal cortisol and stress are associated with birth outcomes, but are not affected by lipid-based nutrient supplements during pregnancy: an analysis of data from a randomized controlled trial in rural Malawi

BackgroundPrenatal micronutrient supplements have been found to increase birth weight, but mechanisms for increased growth are poorly understood. Our hypotheses were that 1) women who receive lipid-based nutrient supplements (LNS) during pregnancy would have lower mean salivary cortisol concentration at 28 wk and 36 wk gestation compared to the multiple micronutrient (MMN) and iron-folic acid (IFA) supplement groups and 2) both salivary cortisol and perceived stress during pregnancy would be associated with shorter duration of gestation and smaller size at birth.MethodsWomen were enrolled in the trial in early pregnancy and randomized to receive LNS, MMN, or iron-folic acid (IFA) supplements daily throughout pregnancy. At enrollment, 28 wk and 36 wk gestation, saliva samples were collected and their cortisol concentration was measured. Self-report of perceived stress was measured using questionnaires. Gestation duration was indicated by ultrasound dating and newborn anthropometric measurements (weight, length, head circumference) provided indicators of intrauterine growth.ResultsOf the 1391 women enrolled in the trial, 1372, 906 and 1049 saliva samples were collected from women at baseline, 28 wk and 36 wk, respectively. There were no significant differences in mean cortisol concentrations by intervention group at 28 wk or 36 wk gestation. Cortisol concentrations were negatively associated with duration of gestation (Baseline: β = −0.05, p = 0.039; 36 wk: β = −0.04, p = 0.037) and birth weight (28 wk: β = −0.08, p = 0.035; 36 wk: β = −0.11, p = 0.003) but not associated with length-for-age or head circumference-for-age z-scores. Perceived stress at 36 wk was significantly associated with shorter newborn LAZ (p = 0.001). There were no significant associations with the risk of small for gestational age, preterm birth, or low birth weight.ConclusionsMaternal salivary cortisol concentration was strongly associated with birth weight and duration of gestation in rural Malawi, but these data do not support the hypothesis that LNS provision to pregnant women would influence their salivary cortisol concentrations.Trial registrationClinicaltrials.gov identifier NCT01239693

Impact of small‐quantity lipid‐based nutrient supplement on hemoglobin, iron status and biomarkers of inflammation in pregnant Ghanaian women

Abstract We examined hemoglobin (Hb, g/L), iron status (zinc protoporphyrin, ZPP, &mgr;mol/mol heme, and transferrin receptor, TfR, mg/L) and inflammation (C‐reactive protein, CRP and alpha‐1 glycoprotein, AGP) in pregnant Ghanaian women who participated in a randomized controlled trial. Women (n = 1320) received either 60 mg Fe + 400‐&mgr;g folic acid (IFA); 18 micronutrients including 20‐mg Fe (MMN) or small‐quantity lipid‐based nutrient supplements (SQ‐LNS, 118 kcal/d) with the same micronutrient levels as in MMN, plus four additional minerals (LNS) daily during pregnancy. Intention‐to‐treat analysis included 349, 354 and 354 women in the IFA, MMN and LNS groups, respectively, with overall baseline mean Hb and anemia (Hb <100) prevalence of 112 and 13.3%, respectively. At 36 gestational weeks, overall Hb was 117, and anemia prevalence was 5.3%. Compared with the IFA group, the LNS and MMN groups had lower mean Hb (120 ± 11 vs. 115 ± 12 and 117 ± 12, respectively; P < 0.001), higher mean ZPP (42 ± 30 vs. 50 ± 29 and 49 ± 30; P = 0.010) and TfR (4.0 ± 1.3 vs. 4.9 ± 1.8 and 4.6 ± 1.7; P < 0.001), and greater prevalence of anemia (2.2% vs. 7.9% and 5.8%; P = 0.019), elevated ZPP (>60) [9.4% vs. 18.6% and 19.2%; P = 0.003] and elevated TfR (>6.0) [9.0% vs. 19.2% and 15.1%; P = 0.004]. CRP and AGP concentrations did not differ among groups. We conclude that among pregnant women in a semi‐urban setting in Ghana, supplementation with SQ‐LNS or MMN containing 20 mg iron resulted in lower Hb and iron status but had no impact on inflammation, when compared with iron (60 mg) plus folic acid (400 &mgr;g). The amount of iron in such supplements that is most effective for improving both maternal Hb/iron status and birth outcomes requires further evaluation. This trial was registered at ClinicalTrials.gov as: NCT00970866.

Effects of a lipid-based nutrient supplement during pregnancy and lactation on maternal plasma fatty acid status and lipid profile: Results of two randomized controlled trials

It is unknown whether a novel small-quantity lipid-based nutrient supplement (SQ-LNS) containing alpha-linolenic (ALA) and linoleic acids impacts maternal plasma lipids and fatty acid status. We measured plasma fatty acids (wt%) and lipid concentrations at 36 wk gestation and breast milk fatty acids (wt%) at 6 months postpartum in a subsample of women enrolled in a randomized controlled trial studying the effects of SQ-LNS on birth outcomes and child growth. Women≤20 wk gestation in Ghana (n=1,320) and Malawi (n=1,391) were assigned to receive daily either: 1) iron-folic acid (pregnancy); 2) multiple micronutrients (pregnancy and lactation); or 3) SQ-LNS (pregnancy and lactation). At 36 wk, plasma ALA levels were higher in those receiving SQ-LNS. SQ-LNS increased breast milk ALA in Ghana but not Malawi. There was no effect on plasma lipids or other selected fatty acids. SQ-LNS may impact plasma and breast milk ALA levels depending on the population.

Predictors and pathways of language and motor development in four prospective cohorts of young children in Ghana, Malawi, and Burkina Faso

Background Previous reviews have identified 44 risk factors for poor early child development (ECD) in low‐ and middle‐income countries. Further understanding of their relative influence and pathways is needed to inform the design of interventions targeting ECD. Methods We conducted path analyses of factors associated with 18‐month language and motor development in four prospective cohorts of children who participated in trials conducted as part of the International Lipid‐Based Nutrient Supplements (iLiNS) Project in Ghana (n = 1,023), Malawi (n = 675 and 1,385), and Burkina Faso (n = 1,122). In two cohorts, women were enrolled during pregnancy. In two cohorts, infants were enrolled at 6 or 9 months. In multiple linear regression and structural equation models (SEM), we examined 22 out of 44 factors identified in previous reviews, plus 12 additional factors expected to be associated with ECD. Results Out of 42 indicators of the 34 factors examined, 6 were associated with 18‐month language and/or motor development in 3 or 4 cohorts: child linear and ponderal growth, variety of play materials, activities with caregivers, dietary diversity, and child hemoglobin/iron status. Factors that were not associated with child development were indicators of maternal Hb/iron status, maternal illness and inflammation during pregnancy, maternal perceived stress and depression, exclusive breastfeeding during 6 months postpartum, and child diarrhea, fever, malaria, and acute respiratory infections. Associations between socioeconomic status and language development were consistently mediated to a greater extent by caregiving practices than by maternal or child biomedical conditions, while this pattern for motor development was not consistent across cohorts. Conclusions Key elements of interventions to ensure quality ECD are likely to be promotion of caregiver activities with children, a variety of play materials, and a diverse diet, and prevention of faltering in linear and ponderal growth and improvement in child hemoglobin/iron status.

Ghanaian parents' perceptions of pre and postnatal nutrient supplements and their effects

Abstract Small‐quantity lipid‐based nutrient supplements (SQ‐LNS) have been studied in efficacy and effectiveness trials, but little is known about how parents perceive the products and their effects. In a randomised trial in Ghana, efficacy of SQ‐LNS provided to women during pregnancy and the first 6 months postpartum and to their children from 6 to 18 months of age was assessed by comparison with iron‐folic acid (IFA) capsules and multiple micronutrient (MMN) capsules provided to women. In a follow‐up study conducted when the index children from the original trial were between 4 and 6 years of age, we used survey‐based methods to assess retrospective and current parental perceptions of nutrient supplements generally and of SQ‐LNS and their effects compared with perceptions IFA and MMN capsules. Most parents perceived that the assigned supplements (SQ‐LNS, IFA, or MMN) positively impacted the mother during pregnancy (approximately 89% of both mothers and fathers) and during lactation (84% of mothers and 86% of fathers). Almost all (≥90%) of mothers and fathers perceived that the assigned supplement positively impacted the index child and expected continued positive impacts on the childs health and human capital into the future. A smaller percentage of parents perceived negative impacts of the supplements (7%–17% of mothers and 4%–12% of fathers). Perceptions of positive impacts and of negative impacts did not differ by intervention group. The results suggest that similar populations would likely be receptive to programs to deliver SQ‐LNS or micronutrient capsules.

Associations of maternal nutrition during pregnancy and post-partum with maternal cognition and caregiving

Abstract Pregnant and post‐partum women require increased nutrient intake and optimal cognition, which depends on adequate nutrition, to enable reasoning and learning for caregiving. We aimed to assess (a) differences in maternal cognition and caregiving between women in Malawi who received different nutritional supplements, (b) 14 effect modifiers, and (c) associations of cognition and caregiving with biomarkers of iron, Vitamin A, B‐vitamin, and fatty acid status. In a randomized controlled trial (n = 869), pregnant women daily received either multiple micronutrients (MMN), 20 g/day lipid‐based nutrient supplements (LNS), or a control iron/folic acid (IFA) tablet. After delivery, supplementation continued in the MMN and LNS arms, and the IFA control group received placebo until 6 months post‐partum, when cognition (n = 712), caregiving behaviour (n = 669), and biomarkers of nutritional status (n = 283) were assessed. In the full group, only one difference was significant: the IFA arm scored 0.22 SD (95% CI [0.01, 0.39], p = .03) higher than the LNS arm in mental rotation. Among subgroups of women with baseline low hemoglobin, poor iron status, or malaria, those who received LNS scored 0.4 to 0.7 SD higher than the IFA arm in verbal fluency. Breastmilk docosahexaenoic acid and Vitamin B12 concentrations were positively associated with verbal fluency and digit span forward (adjusting for covariates ps < .05). In this population in Malawi, maternal supplementation with MMN or LNS did not positively affect maternal cognition or caregiving. Maternal docosahexaenoic acid and B12 status may be important for post‐partum attention and executive function.

Co-causation of reduced newborn size by maternal undernutrition, infections, and inflammation.

Abstract More than 20 million babies are born with low birthweight annually. Small newborns have an increased risk for mortality, growth failure, and other adverse outcomes. Numerous antenatal risk factors for small newborn size have been identified, but individual interventions addressing them have not markedly improved the health outcomes of interest. We tested a hypothesis that in low‐income settings, newborn size is influenced jointly by multiple maternal exposures and characterized pathways associating these exposures with newborn size. This was a prospective cohort study of pregnant women and their offspring nested in an intervention trial in rural Malawi. We collected information on maternal and placental characteristics and used regression analyses, structural equation modelling, and random forest models to build pathway maps for direct and indirect associations between these characteristics and newborn weight‐for‐age Z‐score and length‐for‐age Z‐score. We used multiple imputation to infer values for any missing data. Among 1,179 pregnant women and their babies, newborn weight‐for‐age Z‐score was directly predicted by maternal primiparity, body mass index, and plasma alpha‐1‐acid glycoprotein concentration before 20 weeks of gestation, gestational weight gain, duration of pregnancy, placental weight, and newborn length‐for‐age Z‐score (p < .05). The latter 5 variables were interconnected and were predicted by several more distal determinants. In low‐income conditions like rural Malawi, maternal infections, inflammation, nutrition, and certain constitutional factors jointly influence newborn size. Because of this complex network, comprehensive interventions that concurrently address multiple adverse exposures are more likely to increase mean newborn size than focused interventions targeting only maternal nutrition or specific infections.